Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

Tryptophan and its metabolites in normal physiology and cancer etiology.

Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue-specific expression of Trp-metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme indoleamine 2,3-dioxygenase, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor, which regulates progrowth genes. Moreover, Kyn also inhibits T-cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion and outlines areas for future research focus.

The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of ß-catenin.

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated ß-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of ß-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of ß-catenin. This article has an associated First Person interview with the first authors of the paper.

Co-transmission of Related Malaria Parasite Lineages Shapes Within-Host Parasite Diversity.

In high-transmission regions, we expect parasite lineages within complex malaria infections to be unrelated due to parasite inoculations from different mosquitoes. This project was designed to test this prediction. We generated 485 single-cell genome sequences from fifteen P. falciparum malaria patients from Chikhwawa, Malawi-an area of intense transmission. Patients harbored up to seventeen unique parasite lineages. Surprisingly, parasite lineages within infections tend to be closely related, suggesting that superinfection by repeated mosquito bites is rarer than co-transmission of parasites from a single mosquito. Both closely and distantly related parasites comprise an infection, suggesting sequential transmission of complex infections between multiple hosts. We identified tetrads and reconstructed parental haplotypes, which revealed the inbred ancestry of infections and non-Mendelian inheritance. Our analysis suggests strong barriers to secondary infection and outbreeding amongst malaria parasites from a high transmission setting, providing unexpected insights into the biology and transmission of malaria.

Micetoma por Nocardia sp: reporte del Cusco-Perú / Mycetoma by Nocardia sp: Report from Cusco-Peru

Se reporta el primer caso de micetoma bacteriano por Nocardia sp. en Cusco, Perú. Se trata de un paciente varón de 44 años quien presentó lesión a nivel de extremidad superior derecha. La infección fue controlada con ciprofloxacino en los tres primeros meses, seguido de trimetoprim/ sulfametoxazol por aproximadamente 15 meses. Se observó cicatrización completa de la lesión con formación de cicatrices queloides como secuela en la visita de control a los 20 meses...

We report the first case of bacterial mycetoma caused by nocardia sp., in Cusco, Peru. A 44 years-old male patient presented with a lesion in the upper right limb. Infection was controlled after a 3 month course of ciprofloxacin, followed by trimethoprim/sulfamethoxazole for approximately 15 months. Complete healing of the lesion with keloid scarring as sequel was observed after 20 months...

[Chromomycosis: report of a disabling case]. / Cromomicosis: reporte de un caso incapacitante.

Chromomycosis is a deep subcutaneous mycosis caused by different dymorphic fungi species that normally live in vegetal debris. We report the case of a 51 year-old patient that six years previous to the evaluation worked making roof tiles in Madre de Dios, Peru; where he presented an initial papular lesion in a leg, which continued expanding until the 4 limbs were affected with disabling verrucous lesions. Fumagoid cells were found in the skin biopsy. The patient was hospitalized and received topical cleaning, antibiotics and terbinafine. He was discharged two months later with clinical improvement.

Cromomicosis: reporte de un caso incapacitante / Chromomycosis: report of a disabling case

La cromomicosis es una micosis profunda subcutánea producida por hongos dimórficos que de forma habitual habitan en restos vegetales. Se presenta el caso de un paciente de 51 años que seis años antes del ingreso se dedicaba a la fabricación de tejas en Madre de Dios, Perú; donde sufrió una lesión inicial papular en una pierna la cual se extendió hasta comprometer los cuatro miembros, con lesiones verrucosas que lo llevaron a la discapacidad. Se observaron cuerpos fumagoides en la biopsia de piel. El paciente fue hospitalizado y recibió curaciones tópicas, antibioticoterapia y terbinafina. Fue dado de alta al cabo de dos meses con mejoría clínica.

Chromomycosis is a deep subcutaneous mycosis caused by different dymorphic fungi species that normally live in vegetal debris. We report the case of a 51 year-old patient that six years previous to the evaluation worked making roof tiles in Madre de Dios, Peru; where he presented an initial papular lesion in a leg, which continued expanding until the 4 limbs were affected with disabling verrucous lesions. Fumagoid cells were found in the skin biopsy. The patient was hospitalized and received topical cleaning, antibiotics and terbinafine. He was discharged two months later with clinical improvement.

Las caras del poroma / Poroma's faces

Introducción: El poroma es un tumor benigno de la glándula sudorípara, que se presenta usualmente en plantas y palmas. Se confunde con numerosos cuadros cutáneos y es casi siempre diagnosticado erróneamente. Objetivo: Describir las características clínicas y patológicas de los poromas vistos en el HNSE EsSalud del Cusco entre febrero del 2006 y diciembre del 2008. Tratamos de dar una guía para el enfoque de este tumor. Material y métodos: Estudio descriptivo de ocho casos de poromas que fueron confirmados por histopatología. Adicionalmente en tres casos realizamos estudios con inmunohistoquímica con CEA y EMA. Seis casos fueron tratados con electrocirugía de radiofrecuencia y dos con exéresis convencional. Resultados: Reportamos ocho casos de poromas, cuatro de sexo femenino, con un tiempo de enfermedad entre tres meses y 20 años,dos casos con tiempo de evolución de tres meses se presentaron en mujeres de 25 y 30 años. Siete casos fueron asintomáticos. Cinco casos se ubicaron en miembros inferiores, dos en cuello y uno en cara. La apariencia de las lesiones fue polipoide en un caso, uno con aspecto de placa verrucoide, dos angioides, dos tipo placas anfractuosas, uno fue nodular lobulado oscuro y otro papuloso oscuro. El patrón histopatológico fue epidérmico en dos casos, yuxtaepidérmico en tres y tres correspondieron al tipo dérmico. Tres casos marcaron positivamente con ECA y EMA. La respuesta al tratamiento quirúrgico fue óptima. No se objetivaron recidivas. Conclusiones: Los poromas tienen diversidad clínica, de modo que se pueden confundir con otros cuadros. Es de esperar que ocurran también en adultos jóvenes y en localizaciones insospechadas. Generalmente no dan molestias. El estudio histopatológico es de rigor, mostrando patrones variados, finalmente la inmunohistoquímica afianza el diagnóstico.

Background: Poroma is a benign sweat gland tumor, usually seen in the palm and sole. It may be confused with numerous skin diseases, and it is almost always misdiagnosed. Objective: To describe the clinical and histopathologic features of 8 patients with poroma, seen at the EsSalud National Hospital of Cusco, Peru, between February 2006 and December 2008. We try to give guidance for the management of poromas. Methods: Descriptive study of 8 cases of poroma, confirmed with histopathologic examination. Additionally we made inmunohistochemical evaluation with CEA and EMA in 3 cases. Six patients were treated with radiofrequency surgery and 2 with standard local excision. Results: We report 8 patients with poromas, there were 4 females, with a time of disease between three months and 20 years, the two cases where it was three months occurred in women between 25 and 30. Seven cases were asymptomatic. The lesions in 5 cases were located in the lower limbs, 2 cases in the neck and one in the face. The appearance of the lesions was polypoid in one case, one was a verrucous plaque, 2 had angioid appearance, 2 had simplex plaques, one was a dark multilobulated nodule and one was a dark papule. The histological pattern was epidermic in 2 cases, yuxtaepidermic in 3 and 3 belonged to the dermal type. Three of them marked positive with ECA and EMA. The treatment, mainly with radiosurgery, was satisfactory in all cases. No local recurrences were observed. Conclusions: Poromas have a wide range of clinical presentations, the reason why it can be confused with other conditions. It is also expected to occur in young adults and in unusual locations. They are almost always asymptomatic. Histopatologic evaluation is very important showing varied patterns ant it is immunohistochemistry what ultimately enhances the diagnostic.

Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression.

PURPOSE: Constitutive activation of signal transducer and activator of transcription 3 (Stat3) protein has been observed in a wide variety of tumors, including breast cancer, and contributes to oncogenesis at least in part by prevention of apoptosis. In a study of 45 patients with high-risk breast cancer enrolled in a phase II neoadjuvant chemotherapy trial with docetaxel and doxorubicin, we evaluated the levels of Stat3 activation and potentially associated molecular biomarkers in invasive breast carcinoma compared with matched nonneoplastic tissues. EXPERIMENTAL DESIGN: Using immunohistochemistry and image analysis, we quantified the levels of phospho-Stat3 (pY-Stat3), phospho-Src (pY-Src), epidermal growth factor receptor, HER2/neu, Ki-67, estrogen receptor, Bcl-2, Bcl-xL, Survivin, and apoptosis in formalin-fixed, paraffin-embedded sections from invasive carcinomas and their paired nonneoplastic parenchyma. The levels of molecular biomarkers in nonneoplastic and tumor tissues were analyzed as continuous variables for statistically significant correlations. RESULTS: Levels of activated pY-Stat3 and pY-Src measured by immunohistochemistry were significantly higher in invasive carcinoma than in nonneoplastic tissue (P < 0.001). In tumors, elevated levels of pY-Stat3 correlated with those of pY-Src and Survivin. Levels of pY-Stat3 were higher in partial pathologic responders than in complete pathologic responders. In partial pathologic responders, pY-Stat3 levels correlated with Survivin expression. CONCLUSIONS: Our findings suggest important roles for elevated activities of Stat3 and Src, as well as Survivin expression, in malignant progression of breast cancer. Furthermore, elevated Stat3 activity correlates inversely with complete pathologic response. These findings suggest that specific Stat3 or Src inhibitors could offer clinical benefits to patients with breast cancer.

Cutaneous psammomatous melanotic schwannoma: non-recurrence with surgical excision.

BACKGROUND: Melanotic schwannoma is a pigmented nerve tumor that may be located in the skin and express local aggressivity. This tumor may occur singly. It may also be part of the Carney complex which consists of various, but specific, tumors. OBJECTIVE: We report two cases of subcutaneous melanotic schwannoma localized on the trunk in two men aged 37 and 45 years. METHODS: Conventional histology and immunohistochemistry were performed. RESULTS: One melanotic schwannoma was associated with a cutaneous atypical myxoma and multiple melanocytic lesions, all being part of the Carney complex. The other case had no associated signs. In both cases, the melanotic schwannoma was completely excised and did not recur. CONCLUSION: Melanotic schwannoma is rare and curable by surgery. It must not be confused with malignant melanoma and other pigmented neoplasms. The Carney complex should be carefully ruled out.

Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells.

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cbl. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKTI but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (PI3K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of PI3K or AKT1.

Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells.

Signal transducers and activators of transcription (STATs) were identified originally as key components of cytokine signaling pathways. More recently, constitutive activation of STAT proteins has been detected in a wide variety of human tumor specimens and tumor cell lines. Here, we examined the activation of one STAT family member, Stat3, in human prostate cancer cell lines and primary prostate tumors. An analysis of 45 adenocarcinomas obtained at radical prostatectomy revealed elevated levels of constitutive Stat3 activation in 37 (82%) of 45 of the tumors compared with matched adjacent nontumor prostate tissues. A highly specific immunohistochemical assay for detection of phospho-Stat3 revealed that elevated Stat3 activity was localized primarily in the tumor cells of prostate carcinoma specimens. Furthermore, higher levels of Stat3 activation in patient specimens were correlated significantly with more malignant tumors exhibiting higher Gleason scores. In addition, all of the three human prostate cancer cell lines examined (DU145, PC3, and LNCaP) displayed constitutive activation of Stat3. Substantially lower levels of Stat3 activation were detected in LNCaP cells; however, stimulation with interleukin 6 induced a significant increase in Stat3 DNA-binding activity in these cells. Moreover, the direct inhibition of constitutive Stat3 signaling in DU145 cells using antisense Stat3 oligonucleotides induced growth inhibition and apoptosis. Our findings demonstrate that constitutive activation of Stat3 occurs frequently in primary prostate adenocarcinomas and is critical for the growth and survival of prostate cancer cells. These studies further suggest that Stat3 signaling represents a potentially novel molecular target for prostate cancer therapy.

Carboxy-terminal truncated STAT5 is induced by interleukin-2 and GM-CSF in human neutrophils.

IL-2 and GM-CSF are potent activators of polymorphonuclear neutrophils (PMN) biologic activity. IL-2 and GM-CSF-mediated activation of STAT proteins was examined in nuclear extracts of human PMN. We found that both cytokines induced STAT5-like DNA-binding complexes that could not be supershifted using C-terminal-specific anti-STAT5 antibodies. Therefore, we performed oligoprecipitation experiments with a STAT5-biotinylated DNA probe (biotin-MGFe) and the precipitated proteins were identified by Western immunoblotting. We found that GM-CSF and IL-2 induced the DNA-binding activity of a C-terminal truncated isoform of STAT5. The truncated STAT5 form was present in the nucleus of PMN but the cytoplasmic extracts contained full-length STAT5, suggesting that PMN proteolytically process full-length STAT5 proteins. Proteolytic experiments demonstrated that PMN express a protease activity capable of producing C-terminal processed STAT5 proteins. In many settings, C-terminal truncation of the STAT5 protein leads to inhibition of STAT5 biological activity. Two known STAT5 regulated genes, encoding pim-1 and OSM proteins, failed to be induced by GM-CSF in PMN. These findings provide new insights to a mechanism by which PMN, a terminally differentiated cell, may regulate gene transcription by alternative proteolytic processing.

Metástasis en piel / Metastasis in the skin

Se presenta dos casos de metástasis cutánea, con ilustraciones clínicas y patológicas. Se revisa el tema, se repara en los aspectos importantes de estas manifestaciones y se proporciona recomendaciones de manera sencilla y práctica.